The effect of synbiotic supplementation on plasma levels of advanced glycation end products and cardiovascular risk factors in hemodialysis patients: A double-blind clinical trial.

There is increasing evidence supporting the relationship between imbalance of gut microbiota and development of chronic kidney and cardiovascular diseases. This study aimed to investigate the effect of synbiotic supplementation on plasma levels of advanced glycation end products (AGEs) and cardiovascular risk factors in hemodialysis (HD) patients. In this randomized, double-blind, placebo-controlled clinical trial, 36 HD patients were randomly allocated into two groups to receive two synbiotic supplements ( = 19) or placebo ( = 17) daily for 12 weeks.

The Effect of Synbiotic Supplementation on Bone Complications, Anemia, and Gastrointestinal Function in Hemodialysis Patients: A Double-Blind Randomized Clinical Trial.

Unlabelled: Probiotics affect biomarkers indicative of bone formation, such as alkaline phosphatase (ALP), calcium status, bone mineralization, bone turnover markers and metabolism. This study aims to investigate the effects of synbiotic on gastrointestinal (GI) disorder, bone complications and anemia in hemodialysis (HD) patients. In this randomized, double-blind, placebo-controlled clinical trial study, HD patients received 2 symbiotic (n = 19) or placebo (n = 17) capsules daily for 12 weeks.

Regulation of PKD2 channel function by TACAN.

Autosomal dominant polycystic kidney disease is caused by mutations in the membrane receptor PKD1 or the cation channel PKD2. TACAN (also termed TMEM120A), recently reported as an ion channel in neurons for mechanosensing and pain sensing, is also distributed in diverse non-neuronal tissues, such as kidney, heart and intestine, suggesting its involvement in other functions. In this study, we found that TACAN is in a complex with PKD2 in native renal cell lines.

Do Dipeptidyl Peptidase-4 Inhibitors Increase the Risk of Heart Failure in Patients with Type 2 Diabetes?

Dipeptidyl peptidase-4 inhibitors (DDP-4Is) or gliptins have been extensively studied in recent years. These studies have shown the safety and efficacy of gliptins in managing hyperglycemia in diabetic patients. However, there is an ongoing debate on whether DDP-4Is are associated with a higher risk for developing heart failure.

Cardiac Late Sodium Channel Current Is a Molecular Target for the Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin.

Background: SGLT2 (sodium/glucose cotransporter 2) inhibitors exert robust cardioprotective effects against heart failure in patients with diabetes, and there is intense interest to identify the underlying molecular mechanisms that afford this protection. Because the induction of the late component of the cardiac sodium channel current (late-) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-.

Methods: Electrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question.

Vitamin D is an endogenous partial agonist of the transient receptor potential vanilloid 1 channel.

Key Points: 25-Hydroxyvitamin D (25OHD) is a partial agonist of TRPV1 whereby 25OHD can weakly activate TRPV1 yet antagonize the stimulatory effects of the full TRPV1 agonists capsaicin and oleoyl dopamine. 25OHD binds to TRPV1 within the same vanilloid binding pocket as capsaicin. 25OHD inhibits the potentiating effects of PKC-mediated TRPV1 activity.

Current Views on Dopaminergic Drugs Affecting Glucose Homeostasis.

Background: For more than three decades, it has been known that manipulation of dopaminergic system could affect glucose homesotasis in experimental animals. The notion that glucose homeostasis in human might be influenced by dopaminergic drugs has attracted a great deal of attention in the past two decades. In spite of rapid advancements in revealing involvement of dopaminergic neurotransmission in insulin release, glucose up-take and pancreatic beta cell function in general through centrally and peripherally controlled mechanisms, there are discrepancies among observations on experimental animals and human subjects.

Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2.

Transient receptor potential (TRP) channels are regulated by diverse stimuli comprising thermal, chemical, and mechanical modalities. They are also commonly regulated by phosphatidylinositol-4,5-bisphosphate (PIP2), with underlying mechanisms largely unknown. We here revealed an intramolecular interaction of the TRPP3 N and C termini (N-C) that is functionally essential.

Subcutaneous white adipocytes express a light sensitive signaling pathway mediated via a melanopsin/TRPC channel axis.

Subcutaneous white adipose tissue (scWAT) is the major fat depot in humans and is a central player in regulating whole body metabolism. Skin exposure to UV wavelengths from sunlight is required for Vitamin D synthesis and pigmentation, although it is plausible that longer visible wavelengths that penetrate the skin may regulate scWAT function. In this regard, we discovered a novel blue light-sensitive current in human scWAT that is mediated by melanopsin coupled to transient receptor potential canonical cation channels.

Identification and characterization of hydrophobic gate residues in TRP channels.

Transient receptor potential (TRP) channels, subdivided into 6 subfamilies in mammals, have essential roles in sensory physiology. They respond to remarkably diverse stimuli, comprising thermal, chemical, and mechanical modalities, through opening or closing of channel gates. In this study, we systematically substituted the hydrophobic residues within the distal fragment of pore-lining helix S6 with hydrophilic residues and, based on Xenopus oocyte and mammalian cell electrophysiology and a hydrophobic gate theory, identified hydrophobic gates in TRPV6/V5/V4/C4/M8.

The mechano-sensitivity of cardiac ATP-sensitive potassium channels is mediated by intrinsic MgATPase activity.

Cardiac ATP-sensitive K (K) channel activity plays an important cardio-protective role in regulating excitability in response to metabolic stress. Evidence suggests that these channels are also mechano-sensitive and therefore may couple K channel activity to increased cardiac workloads. However, the molecular mechanism that couples membrane stretch to channel activity is not currently known.

Molecular determinants of ATP-sensitive potassium channel MgATPase activity: diabetes risk variants and diazoxide sensitivity.

ATP-sensitive K(+) (KATP) channels play an important role in insulin secretion. KATP channels possess intrinsic MgATPase activity that is important in regulating channel activity in response to metabolic changes, although the precise structural determinants are not clearly understood. Furthermore, the sulfonylurea receptor 1 (SUR1) S1369A diabetes risk variant increases MgATPase activity, but the molecular mechanisms remain to be determined.

A review on natural products for controlling type 2 diabetes with an emphasis on their mechanisms of actions.

The use of natural products is very common among non-industrialized societies because these remedies are more accessible and affordable than modern pharmaceuticals. In developed countries, use of herbal products has recently increased as scientific evidence about their effectiveness has become broadly available. For the past two decades many research articles in the field of ethno-pharmacology have focused on the anti-diabetic effects of some natural products.

Late sodium current inhibition alone with ranolazine is sufficient to reduce ischemia- and cardiac glycoside-induced calcium overload and contractile dysfunction mediated by reverse-mode sodium/calcium exchange.

Excessive reverse-mode (RM) sodium/calcium exchanger 1.1 (NCX1.1) activity, resulting from intracellular sodium accumulation caused by reduced Na+/K+-ATPase activity, increased Na-H exchanger 1 activity.

Intravitreal triamcinolone for acute branch retinal vein occlusion: a randomized clinical trial.

Purpose: To evaluate the therapeutic effect of intravitreal triamcinolone (IVT) injection for recent branch retinal vein occlusion (BRVO).

Methods: In a randomized controlled clinical trial, 30 phakic eyes with recent (less than 10 weeks' duration) BRVO were assigned to two groups. The treatment group (16 eyes) received 4 mg IVT and the control group (14 eyes) received subconjunctival sham injections.

Pharmacogenomic analysis of ATP-sensitive potassium channels coexpressing the common type 2 diabetes risk variants E23K and S1369A.

Objectives: The common ATP-sensitive potassium (KATP) channel variants E23K and S1369A, found in the KCNJ11 and ABCC8 genes, respectively, form a haplotype that is associated with an increased risk for type 2 diabetes. Our previous studies showed that KATP channel inhibition by the A-site sulfonylurea gliclazide was increased in the K23/A1369 haplotype. Therefore, we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure-activity relationships in KATP channels containing either the E23/S1369 nonrisk or K23/A1369 risk haplotypes.

The ATP-sensitive K(+) channel ABCC8 S1369A type 2 diabetes risk variant increases MgATPase activity.

Pancreatic β-cell ATP-sensitive K(+) (K(ATP)) channels are composed of Kir6.2 and SUR1 subunits encoded by the KCNJ11 and ABCC8 genes, respectively. Although rare monogenic activating mutations in these genes cause overt neonatal diabetes, the common variants E23K (KCNJ11) and S1369A (ABCC8) form a tightly heritable haplotype that is associated with an increased susceptibility to type 2 diabetes (T2D) risk.

Novel residues lining the CFTR chloride channel pore identified by functional modification of introduced cysteines.

Substituted cysteine accessibility mutagenesis (SCAM) has been used widely to identify pore-lining amino acid side chains in ion channel proteins. However, functional effects on permeation and gating can be difficult to separate, leading to uncertainty concerning the location of reactive cysteine side chains. We have combined SCAM with investigation of the charge-dependent effects of methanethiosulfonate (MTS) reagents on the functional permeation properties of cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels.

Mechanism of direct bicarbonate transport by the CFTR anion channel.

Background: CFTR contributes to HCO(3)(-) transport in epithelial cells both directly (by HCO(3)(-) permeation through the channel) and indirectly (by regulating Cl(-)/HCO(3)(-) exchange proteins). While loss of HCO(3)(-) transport is highly relevant to cystic fibrosis, the relative importance of direct and indirect HCO(3)(-) transport it is currently unknown.

Methods: Patch clamp recordings from membrane patches excised from cells heterologously expressing wild type and mutant forms of human CFTR were used to isolate directly CFTR-mediated HCO(3)(-) transport and characterize its functional properties.

Identification of positive charges situated at the outer mouth of the CFTR chloride channel pore.

We have used site-directed mutagenesis and functional analysis to identify positively charged amino acid residues in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel that interact with extracellular anions. Mutation of two positively charged arginine residues in the first extracellular loop (ECL) of CFTR, R104, and R117, as well as lysine residue K335 in the sixth transmembrane region, leads to inward rectification of the current-voltage relationship and decreased single channel conductance. These effects are dependent on the charge of the substituted side chain and on the Cl(-) concentration, suggesting that these positive charges normally act to concentrate extracellular Cl(-) ions near the outer mouth of the pore.

State-dependent access of anions to the cystic fibrosis transmembrane conductance regulator chloride channel pore.

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is gated by intracellular factors; however, conformational changes in the channel pore associated with channel activation have not been identified. We have used patch clamp recording to investigate the state-dependent accessibility of substituted cysteine residues in the CFTR channel pore to a range of cysteine-reactive reagents applied to the extracellular side of the membrane. Using functional modification of the channel current-voltage relationship as a marker of modification, we find that several positively charged reagents are able to penetrate deeply into the pore from the outside irrespective of whether or not the channels have been activated.

Effects of 17beta-estradiol on neuronal cell excitability and neurotransmission in the suprachiasmatic nucleus of rat.

17beta-Estradiol receptors have been found in several brain nuclei including the suprachiasmatic nucleus (SCN) of mammalian species. The SCN is believed to act as brain clock regulating circadian and circannual biological rhythms, such as body temperature, sleep, and mood. Here, we examined whether 17beta-estradiol (E2) could affect cell excitability and synaptic transmission in the SCN.

Direct and indirect effects of mutations at the outer mouth of the cystic fibrosis transmembrane conductance regulator chloride channel pore.

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel pore is thought to contain multiple binding sites for permeant and impermeant anions. Here, we investigate the effects of mutation of different positively charged residues in the pore on current inhibition by impermeant Pt(NO(2)) (4) (2-) and suramin anions. We show that mutations that remove positive charges (K95, R303) influence interactions with intracellular, but not extracellular, Pt(NO(2))(4)(2-) ions, consistent with these residues being situated within the pore inner vestibule.